Sentinel Lymph Node Biopsy in Patients With Melanoma

Updated: Jul 25, 2019
  • Author: Amy E Somerset, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Overview

Practice Essentials

The incidence of melanoma has risen in the last three decades, with an estimated 96,480 new melanoma diagnoses in 2019, with about 7,230 deaths. [1]  Survival rates are profoundly affected by the stage at time of diagnosis as determined by nodal involvement. Biopsy of sentinel lymph nodes (SLNs)—the first lymph nodes involved in lymphatic spread—can predict the potential for cancer in the local nodal basin or beyond. Sentinel node histology reflects the histology of the remainder of the lymphatic basin. SLN biopsy (SLNB) (see the image below) is associated with significantly fewer complications than regional lymphadenectomy and is recommended for patients at risk for metastasis. SLNB provides important information for both prognosis and further treatment.

Intraoperative left axillary sentinel lymph node s Intraoperative left axillary sentinel lymph node seen after uptake with blue dye.

For each recommendation, a thorough discussion with the patient should be undertaken regarding the risks and benefits of performing SLNB.

Indications for SLNB

SLNB should not be offered for melanoma in situ, where the cancer cells are confined to the epidermis.

SLNB should not be recommended routinely for thin melanomas that are T1a (nonulcerated lesions < 0.8 mm Breslow thickness).

SLNB should be considered for thin melanomas that are T1b (0.8 to 1-mm thickness or < 0.8 mm with ulceration).

SLNB should be recommended to patients with a clinically negative nodal basin and intermediate thickness primary melanomas (T2 or T3; >1 mm to 4 mm).

SLNB should be considered for thick melanomas (T4; >4 mm) and clinically negative nodes.

SLNB may be considered for melanoma that exhibits regression (controversial).

Potential contraindications for SLNB

SLNB is unnecessary if systemic disease is present.

SLNB may not be reliable if there has been previous extensive surgery in the targeted lymph node basin.

Fine-needle aspiration (FNA) or core needle biopsy of the node is preferable to SLNB as a first step when a clinically evident node is present.

There is debate about SLNB following a wide local excision; however, it may be acceptable if extensive reconstruction has not been performed.

Some suggest that repeat SLNB following a prior SLNB is inadvisable; however, no definitive recommendations exist in the melanoma literature. The authors do not consider prior SLNB a contraindication for repeat biopsy.

Staging

Clinical staging of melanoma commonly involves the tumor, node, metastasis (TNM) staging system as developed by the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC). This system incorporates the primary tumor (T), lymph nodes (N), and distant metastases (M). Clinical staging is based on physical examination and lesion biopsy.

Clinical staging is as follows:

  • Stage 0: TisN0M0
  • Stage IA: T1aN0M0
  • Stage IB: T1bN0M0; T2aN0M0
  • Stage IIA: T2bN0M0; T3aN0M0
  • Stage IIB: T3bN0M0; T4aN0M0
  • Stage IIC: T4bN0M0
  • Stage III: Any T, ≥N1, M0
  • Stage IV: Any T, Any N, M1

Pathologic staging is as follows:

  • Stage 0: TisN0M0
  • Stage IA: T1aN0M0
  • Stage IIA: T2bN0M0; T3aN0M0
  • Stage IB: T1bN0M0; T2aN0M0
  • Stage IIB: T3bN0M0; T4aN0M0
  • Stage IIC: T4bN0M0
  • Stage IIIA: T1a-2a, N1a/2a, M0
  • Stage IIIB: T0-2a, N1b-c, M0; T1a-2a, N2b, M0; T2b-3a, N1a-2b, M0
  • Stage IIIC: T0, N2b-c/3b-c, M0; T1a-3a, N2c-3c, M0; T3b-4a, Any N, M0; T4b, N1a-2c, M0
  • Stage IIID: T4b, N3a-c, M0
  • Stage IV: Any T, Any N, M1

Procedure

The main elements of SLNB are as follows:

  • Preoperative intradermal injection of a technetium TC-99–labeled lymphatic mapping agent around the primary melanoma followed by lymphoscintigraphy to image lymphatic drainage patterns
  • Transport to the operative suite and induction of anesthesia
  • Optional intradermal injection of approximately 1 mL of blue dye (isosulfan blue or methylene blue [preferred]) at the site of the primary melanoma followed by massage of the lesion for 4-5 minutes to enhance lymphatic drainage
  • Use of a handheld gamma probe to identify “hot spots” with high radiotracer activity (ie, sentinel nodes)
  • Placement of a small incision overlying the hot spot; incisions should be planned to allow for further dissection if this proves necessary
  • Use of a handheld gamma probe to identify hot nodes in the field and guide dissection; visual search for grossly blue nodes (guided by blue lymphatics) may assist if dye injected
  • Removal of any nodes with significant radiotracer activity, followed by ex vivo measurement of their radioactivity
  • Collection of SLNs (defined as any nodes that are grossly suspicious, harbor blue dye, or have a radioactivity count >10% of the hottest node value) for histologic evaluation, including serial sectioning and appropriate staining
  • Continuation of dissection until the nodal bed count is 10% of that of the hottest node removed (awareness that after four negative nodes, subsequent nodes are very unlikely to be positive)
  • Wide local excision of the primary melanoma; may be prior to or after completion of SLNB

Postprocedure follow up is as follows:

  • All patients: At least annual skin examination for life; regular self-skin and lymph node examination; routine blood tests not recommended
  • Stage I-IIA: Physical examinations with attention to skin and lymph nodes every 6-12 months for 5 years, then annually; routine radiologic surveillance not recommended
  • Stage IIB-IV: Examinations every 3-6 months for 2 years, then every 3-12 months for 3 years, then annually; consider imaging every 3-12 months to screen for recurrence or metastasis (not recommended after 3-5 years)

Follow up is dictated by the stage of disease, as outlined by the National Comprehensive Cancer Network (NCCN) (Guidelines Version 2.2019).

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Background

Although it has been known since the time of Hippocrates, melanoma was not described in Western literature until recognized by John Hunter in 1787. It was not until 1968 that specimens were examined microscopically when Dr. Bodenham confirmed that the “black cancer” described by Hunter was in fact melanoma. [2] Melanoma is a lethal disease that continues to rise in incidence.

The American Cancer Society’s estimates for melanoma include 96,480 new melanoma diagnoses in 2019, with about 7,230 deaths. [1] Melanoma is one of fastest growing cancers and its incidence has continued to rise for the last few decades. It is also one of the most common malignancies in patients younger than 30 years, surpassing cervical cancer in young women.

Risk factors for development of melanoma include multiple clinically atypical moles or dysplastic nevi, family history, prior melanoma, inherited genetic mutations, and sun exposure. [3, 4] Although melanoma often arises in patients with fair skin and with significant sun exposure, it can affect any ethnicity and areas of the body with limited sun exposure. [5]

The concept of lymphatic spread of cancer has been known for quite some time. Accordingly, it was reasoned that removing lymph nodes before the spread of melanoma could prevent systemic disease. In 1898, Snow published his work on the concept of “anticipatory gland excision,” or what would be later known as elective lymph node dissection (ELND). [6] Although Snow’s reasoning was sound, multiple randomized controlled trials, short of subset analysis, showed no beneficial effect on survival or local control. [7, 8, 9] These trials were performed mainly on intermediate-depth melanomas (1-4 mm). In patients with thin melanomas (< 1 mm), the rate of nodal involvement seemed low enough that an ELND was not warranted. [10] For thicker melanomas (>4 mm), the risk of systemic metastasis appeared to outweigh the potential benefit of ELND. [11]

In 1955, Seaman and Powers used radiolabeled colloidal gold to describe the path of lymphatic channels followed by cancer. [12] Subsequent studies by Gould et al described the first node involved in lymphatic spread, which was then termed the sentinel lymph node (SLN). [13] Finally, in 1992, Morton et al showed that the SLN could accurately predict the potential for cancer in the associated nodal basin. [14]

Although the complex anatomy and lymphatic drainage of the head and neck (see Anatomic Considerations) can make treatment of melanoma in this area quite challenging, SLN biopsy (SLNB) can be performed with acceptable morbidity. SLNB carries profound prognostic implications and dictates subsequent therapeutic decisions. The impact of further therapy in patients with a positive SLN (eg, completion lymph node dissection [CLND] and/or systemic therapy) remains an active area of investigation.

For more information, see Malignant Melanoma, Head and Neck Mucosal Melanomas, and Malignant Melanoma Staging.

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Indications

Sentinel lymph node biopsy (SLNB) should be offered to all patients with a clinically negative nodal basin and a primary melanoma greater than 1 mm in depth. As noted, evaluation of the nodal basins via elective lymph node dissection (ELND) was most commonly limited to melanoma with a depth of 1-4 mm. Biopsy of the sentinel node carries a lower risk of morbidity in comparison to a more extensive lymph node dissection. This has allowed for the expansion of the indications for evaluation of the nodal basins associated with melanoma, and SLNB should be routinely recommended for patients with 1-4 mm thick lesions (T2-T3).

Patients with melanomas less than or equal to 1 mm in thickness are at lower risk for nodal involvement (2-5%), [15] and there is debate as to whether they would benefit from evaluation of the regional nodal basin. Currently, the National Comprehensive Cancer Network (NCCN) recommends against SLNB for patients with melanoma in situ (stage 0) or melanoma less than 0.8 mm in thickness (stage IA). Patients with melanoma 0.8-1.0 mm in thickness (T1b) may be considered for SLNB if adverse features such as ulceration, positive deep margins, lymphovascular invasion, age younger than 40 years, significant vertical growth phase, increased mitotic rate, and Clark level IV or higher are present. [5] Patients with melanoma exhibiting regression may also be considered for SLNB, although this is more controversial. Some studies have indicated that there may be no association between regression and positive SLN status. [16, 17, 18]

SLNB may also be offered to patients with deep (>4 mm; T4) melanoma and clinically negative nodes, as it has proven to yield valuable prognostic information, with rates of positive SLNs ranging from 30-40%. [19, 20] The choice of adjuvant therapy or clinical trial enrollment for patients with very thick melanomas may be influenced by SLNB results.

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Contraindications

Sentinel lymph node biopsy (SLNB) is not always warranted. It may be deemed unnecessary when patients present with systemic disease, as it does not alter treatment and does not offer any survival advantage. If a patient presents with a clinically evident node, the first step should be evaluation of that node with fine-needle aspiration (FNA) or core needle biopsy as opposed to SLNB. [5]

Whether SLNB should be performed after a wide local excision is somewhat controversial as there is concern the lymphatics may be altered. It appears, however, that if extensive reconstruction has not been performed, SLNB can be used in patients with a prior wide local excision. [21, 22]

For patients who have previously undergone SLNB, there is nothing in the melanoma literature to establish definitive recommendations. The breast cancer literature suggests that SLNB may be feasible, [23] but whether such limited data can be applied to melanoma patients is a matter of debate. Nevertheless, given the reliability of lymphatic mapping for the identification of nodal pathways, the authors believe that prior SLNB is not a contraindication to repeat biopsy.

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Guidelines

Guidelines from the American Society of Clinical Oncology and Society of Surgical Oncology are as follows [24] :

  • Routine sentinel lymph node biopsy (SLNB) not recommended for T1a melanomas (nonulcerated lesions < 0.8 mm in Breslow thickness)
  • SLNB considered for T1b melanomas (0.8-1 mm Breslow thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with patient about potential benefits and risks associated with the procedure
  • SLNB recommended for T2 and T3 melanomas (Breslow thickness of >1 mm to 4 mm)
  • SLNB may be recommended for T4 melanomas (>4 mm in Breslow thickness), after a discussion of potential benefits and risks
  • In the case of a positive SLNB,  completion lymph node dissection (CLND) or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathologic factors; for higher-risk patients, careful observation may be considered only after a thorough discussion with patients about potential risks and benefits of foregoing CLND
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Anatomic Considerations

Anatomically following the lymphatic channels below the neck is relatively straightforward. The lymphatics follow the path toward either the ipsilateral axilla or groin in the upper and lower extremities, respectively. Clinicians should be aware that although the majority of sentinel lymph nodes (SLNs) are found in the major nodal basins, some can also be found in the epitrochlear nodal basin in the upper extremities and the popliteal nodal basin in the lower extremities.

In the truncal region, lymphatic pathways can travel to multiple nodal basins. This highlights the value of SLN mapping, which eliminates some of the guesswork for determination of melanoma spread. It is important, however, to keep in mind that nodes may be found anywhere along the line from the melanoma site to the nodal basin and that any of these nodes has the potential to harbor metastasis. [25]

The lymphatic drainage of the head and neck is more extensive and variable than that of the trunk or extremities. The lymphatic drainage of the anterior neck is based on a system developed at Memorial Sloan-Kettering in the 1930s. Seven levels of lymph nodes exist (see the image below).

Lateral cervical lymph nodes I-VI. Level VII nodes Lateral cervical lymph nodes I-VI. Level VII nodes are not shown.

Levels I-V describe the lateral neck lymph node basins, while levels VI and VII describe the central lymph node basins, as follows:

  • Level I: Submandibular nodes, which lie between the mandible and the posterior and anterior bellies of the digastric muscle
  • Level II: Upper jugular nodes, which lie between the skull and the hyoid bone along the internal jugular vein
  • Level III: Middle jugular nodes, which lie between the hyoid bone and the omohyoid muscle along the internal jugular vein
  • Level IV: Lower jugular nodes, which lie between the omohyoid muscle and the clavicle along the internal jugular vein
  • Level V: Posterior triangle nodes, which lie between the trapezius and the sternocleidomastoid muscle above the clavicle
  • Level VI: Centrally located nodes between the carotid sheath and above the suprasternal notch
  • Level VII: Superior mediastinal nodes, which lie below the suprasternal notch

Traditionally, a line that bisected the ear caudad to cephalad marked the boundaries of the anterior and posterior drainage of the scalp (see the image below). Lesions anterior to this line would drain to the parotid, submandibular, and cervical lymph nodes (levels I-V). Lesions posterior to this line would drain to the posterior auricular, suboccipital, upper jugular, and posterior triangle lymph nodes. It was assumed that lymphatic drainage would not cross the midline.

Drainage patterns of the scalp. Drainage patterns of the scalp.

The advent of lymphoscintigraphy, however, demonstrated that these assumptions are not always accurate. In 1994, Wells et al found that lymphoscintigraphy was discordant with clinical predictions of nodal drainage 84% of the time. [26] Even after revision of the clinical parameters, a study by O’Brien et al the following year still found a discordance rate of 33%. [27] Uren also reported discordance rates of 33% and demonstrated nodal basins draining across midline in 10% of cases. [28]

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Staging

The staging of melanoma has undergone multiple changes. Common staging is according to the tumor, node, metastasis (TNM) system of the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC). [29] Changes were made to the 8th edition, which are included in the Table below. Stage groupings are as above.

Table. AJCC TNM Classification of Melanoma (Open Table in a new window)

T

Thickness, mm

Ulceration Status/Mitosis

Tis

n/a

n/a

T1

< 0.8

0.8-1

a: Without ulceration 

b: < 0.8 with ulceration or 0.8-1 with or without ulceration

T2

>1-2

a: Without ulceration

b: With ulceration

T3

>2-4

a: Without ulceration

b: With ulceration

T4

>4

a: Without ulceration

b: With ulceration

N

No. of Metastatic Nodes or Microsatellite, Satellite, or In-transit Metastasis (MSI)

Nodal Metastatic Burden

NX

N0

Regional lymph nodes not assessed

0

No lymph node spread

N1

1

a: 1 clinically occult, no MSI

b: 1 clinically detected, no MSI

c: No regional lymph node disease, but MSI present

N2

2-3

a: 2-3 clinically occult, no MSI

b: 2-3 with at least 1 clinically detected

c: 1 clinically occult or clinically detected and MSI present

N3

≥4

a: ≥4 clinically occult, no MSI

b: ≥4 at least 1 clinically detected or any number of nodes stuck together, no MSI

c: ≥2 clinically occult or clinically detected and MSI present

M

Site

Lactate Dehydrogenase Level

M0

No distant metastases

n/a

M1a

Distant skin, soft tissue, and/or nonregional lymph node

M1a(0) Not elevated

M1a(1) Elevated

M1b

Lung metastasis with or without M1a sites of disease

M1b(0) Not elevated

M1b(1) Elevated

M1c

Non-CNS visceral metastases with or without M1a or M1b sites of disease

M1c(0) Not elevated

M1c(1) Elevated

M1d

Distant to CNS with or without M1a, M1b, or M1c sites of disease

M1d(0) Not elevated

M1d(1) Elevated

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Outcomes

A positive sentinel lymph node (SLN) carries extremely valuable prognostic information. Survival rates for patients with a negative SLN have been shown to be superior to those with a positive SLN. In addition, the method of detection has been shown to be a predictor of survival as well. SLNs that are positive only on polymerase chain reaction (PCR) are associated with a better survival rate than those detected with hematoxylin and eosin (H&E) staining (see the image below). [30]

Survival rates of negative sentinel lymph node ver Survival rates of negative sentinel lymph node versus detection by polymerase chain reaction (PCR) and detection by PCR and H&E.

In patients with a positive SLN, previous recommendations were to perform  completion lymph node dissection (CLND) and treat with adjuvant interferon—this was the first adjuvant therapy to show benefit in patients with positive nodes. There have since been major advances in immunotherapy for melanoma, and monoclonal antibodies like ipilimumab have shown equivalent efficacy. More recent studies show protein kinase (PK) inhibitors may be superior as adjuvant therapy and for stage IV disease. There has been identification of several drug targets for the treatment of stage IV disease, with newer drugs inhibiting BRAF, MEK, NRAS, and KIT. Significant clinical benefit has been seen for patient with BRAF mutations, although the most superior systemic therapy has not been established.

There is no question that SLNB provides tremendous prognostic information but the actual degree of sentinel node disease that would benefit from treatment is not known.  Some studies have shown that a small volume of disease within the SLN is rarely associated with disease in other lymph nodes. Some suggest that even a small amount of disease is associated with recurrence and decreased survival compared to patients with no SLN disease.  The MSLT-II trial confirmed prior studies showing that, with current treatment paradigms, while immediate CLND reduces regional recurrence slightly (i.e., improves regional control), it does not increase melanoma-specific survival. [31]   Thus, current NCCN Guidelines indicate both nodal basin surveillance and CLND as primary treatment options in the setting of a microscopically positive SLN, with adjuvant systemic therapy vs. observation.  The threshold of disease at which patients truly benefit from further surgical or immunologic treatment has not been determined.

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